Lysophosphatidic acid

Overview: Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Lysophospholipid Receptors; Chun et al., 2002) are activated by the endogenous lipid derivative LPA. Originally identified as members of the endothelial differentiation gene (edg) family along with sphingosine 1-phosphate receptors, the gene names have recently been updated to LPAR1, etc. to reflect the receptor function of these proteins. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Radioligand binding has been conducted in heterologous expression systems using [³H]-LPA (e.g. Fukushima et al., 1998). In native systems, analysis of binding data is complicated by metabolism and high levels of nonspecific binding, and therefore the relationship between recombinant and endogenously expressed receptors is unclear. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. LPA has also been described to be an agonist at PPARγ receptors (McIntyre et al., 2003), although the physiological significance of this observation remains unclear (Simon et al., 2005). A probable sixth LPA receptor, LPA₆, has been recently reported (Yanagida et al., 2009).

Nomenclature	LPA1	LPA2	LPA3	LPA4	LPA5
Other names	VZG-1, Edg2, lpA1	Edg4, lpA2	Edg7, lpA3	p2y9, gpr23	GPR92
Ensembl ID	ENSG00000119438	ENSG00000064547	ENSG00000171517	ENSG00000147149	ENSG00000184574
Principal transduction	Gi/o, Gq/11, G12/13	Gi/o, Gq/11, G12/13	Gi/o, Gq/11, Gs	Gi/o, Gq/11, Gs, G12/13 (Lee et al., 2007)	Gq, G12/13 (Kotarsky et al., 2006; Lee et al., 2006)
Selective agonists	–	FAP10, FAP12 (Virag et al., 2003)	OMPT (Hasegawa et al., 2003)	–	–
Selective antagonists	Ki16425 (Ohta et al., 2003)	–	DGPP 8:0 (Ohta et al., 2003)	–	–

FAP12, VPC12249 and VPC32179 have antagonist activity at LPA₁ and LPA₃ receptors (Okusa et al., 2003; Virag et al., 2003; Bagga et al., 2004). The selectivity of these antagonists is less than two orders of magnitude. None of the currently available chemical tools have validated specificity in vivo.

Glossary

Abbreviations:

DGPP 8:0

dioctanoylglycerol pyrophosphate

FAP10

decanol phosphate

FAP12

dodecanol phosphate

Ki16425

3-(4-[4-{(1-[2-chlorophenyl]ethoxy)carbonylamino}-3-methyl-5-isoxazolyl]benzylsulfanyl)propanoic acid

OMPT

1-oleoyl-2-O-methyl-rac-glycerophosphothionate

VPC12249

(S)-phosphoric acid mono-[3-(4-benzyloxy-phenyl)-2-octadec-9-enoylamino-propyl] ester

VPC32179

(R)-phosphoric acid mono-{2-octadec-9-enoylamino-3-[4-(pyridin-2-ylmethoxy)-phenyl]-propyl} ester

Further Reading

Aoki J, Inoue A, Okudaira S (2008). Two pathways for lysophosphatidic acid production. Biochim Biophys Acta1781: 513–518.

Chun J, Rosen H (2006). Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases. Curr Pharm Des12: 161–171.

Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W et al. (2002). International Union of Pharmacology. XXXIV. Lysophospholipid Receptor Nomenclature. Pharmacol Rev54: 265–269.

Gardell SE, Dubin AE, Chun J (2006). Emerging medicinal roles for lysophospholipid signaling. Trends Mol Med12: 65–75.

Ishii S, Noguchi K, Yanagida K (2009). Non-Edg family lysophosphatidic acid (LPA) receptors. Prostaglandins Other Lipid Mediat89: 57–65.

Lin DA, Boyce JA (2006). Lysophospholipids as mediators of immunity. Adv Immunol89: 141–167.

Meyer Zu Heringdorf D, Jakobs KH (2007). Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim Biophys Acta1768: 923–940.

Mutoh T, Chun J (2008). Lysophospholipid activation of G protein-coupled receptors. Subcell Biochem49: 269–297.

Noguchi K, Herr D, Mutoh T, Chun J (2009). Lysophosphatidic acid (LPA) and its receptors. Curr Opin Pharmacol9: 15–23.

Pyne NJ, Pyne S (2008). Sphingosine 1-phosphate, lysophosphatidic acid and growth factor signaling and termination. Biochim Biophys Acta1781: 467–476.